This research program is directed toward the design and development of general tactics and strategies for the efficient syntheses of natural and unnatural products that exhibit significant biological activities. Specific objectives include the syntheses of the aloe-derived natural product 5-hydroxyaloin A, the anticancer agents vineomycinone B 2, kidamycin and rubiflavin A, the farnesyl transferase inhibitors solandelactone E and solandelactone F, and tremulenediol A, which was isolated from a fungal pathogen. Unnatural analogues of rubiflavin A will be prepared to determine the effects of modifying the sugars and side chain stereochemistry upon DNA binding properties; these compounds will also be used as probes of TATA box dependent transcription. The potential of unnatural C-aryl glycosides as glycoepitope mimics will be evaluated by preparing and testing C-glycoside analogues as antagonists of sialyl LewisX-selectin interactions. The synthetic plan for each target involves development and application of new synthetic methodology. For example, the approaches to the C-aryl glycosides 5-hydroxyaloin A, vineomycinone B 2, kidamycin and rubiflavin A feature intramolecular [4+2] cycloadditions of sugar-substituted furans with benzynes to give oxabicycloheptadienes that undergo acid-catalyzed rearrangements to furnish C-glycosylated naphthols. New catalytic protocols for introducing sugars onto benzyne-furan adducts via SN2' opening/oxidation will also be developed. The unified strategy for the syntheses of solandelactones E and F is stereoselective and convergent and allows access to all solandelactones from a common intermediate. The synthesis of tremulenediol A features a novel series of reactions involving an enantioselective cyclopropanation to give a vinyl cyclopropyl lactone that undergoes SN2' opening giving a product that may be transformed via [5+2] cycloaddition to deliver the requisite bicyclo[5.3.0] ring system. In the context of this work, new catalytic processes involving metal-catalyzed allylic SN2 substitutions followed by tandem cycloisomerizations and Pauson-Khand reactions will be developed. Quantities of the natural products and selected congeners will be prepared for submission to Merck Research Laboratories, Abbott Laboratories, Wyeth, Pfizer, Inc., and Professor Laurence Hurley (University of Arizona) for biological testing and evaluation.